Page 385 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

352 SECTION | III Nanoparticles, Radiation and Carcinogens

VetBooks.ir affects repeat sequences, leading to increased genomic hematopoietic malignancies; miR-17-92 cluster, which tar-
gets the proapoptotic gene Bim and is overexpressed in
instability by promoting chromosomal rearrangements.
many different types of cancers. In contrast to oncomirs,
Additionally, hypomethylation of retrotransposons can
result in their activation and translocation to other geno- tumor suppressor miRNAs target oncogenes and growth
mic regions, thus increasing genomic instability. DNA promoting pathways, and are often down-regulated in
hypomethylation can activate growth promoting genes cancers. For example, miR-15 and miR-16 target the antia-
(proto-oncogenes), thereby inappropriately turning on poptotic gene BCL2 and are down-regulated in chronic
mitogenic signals. DNA hypomethylation can also lead to lymphocytic leukemia; miR-127 targets BCL6 and is
the loss of genomic imprinting. In contrast, site-specific down-regulated in prostate and bladder tumors (Sharma
hypermethylation can contribute to tumorigenesis by et al., 2010).
silencing tumor suppressor genes (Sharma et al., 2010). Clearly, the normal cellular epigenetic landscape is
Silencing of gene expression in carcinogenesis also significantly altered in cancer. The underlying mechan-
involves global loss of transcription-activating histone isms that initiate these global changes are not fully under-
modifications, such as acetylation and activating methyla- stood, and neither are the causative versus correlative
tion. All known histone acetylations are transcription- nature of the changes observed. Nevertheless, recent stud-
activating. In contrast, certain histone methylations are ies indicate that some changes occur very early in cancer
transcription-activating, such as histone H4 lysine 20 meth- development and may contribute to cancer initiation
ylation, whereas others are transcription-repressing, such as (Jones and Baylin, 2007; Sharma et al., 2010).
histone H3 lysine 9 and lysine 27 methylation. Loss of his-
tone acetylation is carried out by histone deacetylase CLASSIFICATION OF CARCINOGENS
(HDAC), which is often overexpressed in various types of
cancer (Sharma et al., 2010). In addition to the loss of The most widely used system for classifying carcinogens
transcription-activating modifications, cancer cells also comes from the International Agency for Research on
have active transcriptional silencing modifications as well, Cancer (IARC). The US Environmental Protection Agency
such as histone H3 lysine 9 and lysine 27 methylation. (EPA) has also developed a very similar classification
The third arm of epigenetic regulation, the RNA inter- scheme. In the past 30 years, IARC has evaluated nearly
ference caused by miRNA, also shows widespread dysre- 1000 chemicals for their cancer-causing potential in
gulation of expression in carcinogenesis. Because miRNAs humans. Most of the chemicals that IARC evaluated are
are involved in transcriptional regulation, cell proliferation classified as probably or possibly carcinogenic or not classi-
and apoptosis, dysregulation in their expression can pro- fiable. About 12% are classified as carcinogenic to humans.
mote tumorigenesis. Oncogenic miRNAs (oncomirs) target The IARC classification scheme is described in Table 20.5.
tumor suppressors and growth inhibitory pathways and are
often up-regulated in various types of cancer. Examples of ASSAYS FOR CARCINOGENS
oncomirs are miR-21 (targets the tumor suppressor “phos-
phatase and tensin homolog deleted on chromosome 10” Tests most frequently used to determine the carcinogenic
(PTEN)), which is upregulated in human glioblastoma; potential include (1) long term rodent cancer bioassays
miR-155, which is upregulated in breast, lung and several and (2) short term assays.

TABLE 20.5 IARC Classification of Human Carcinogens

Carcinogen Classification Explanation
Group 1 Known human carcinogen Sufficient evidence of carcinogenicity in humans
Group 2A Probable human Limited evidence of carcinogenicity in humans; sufficient evidence in experimental animals,
carcinogen and strong evidence that carcinogenesis in experimental animals is mediated by a mechanism
that also operates in humans
Group 2B Possible human Limited evidence of carcinogenicity in humans, and less than sufficient evidence of
carcinogen carcinogenicity in experimental animals
Group 3 Not classifiable for human The evidence of carcinogenicity is inadequate or limited in experimental animals
carcinogenicity
Group 4 Not likely to be a human Not carcinogenic to humans
carcinogen